Interactive Associations between <i>PPARγ</i> and <i>PPARGC1A</i> and Bisphosphonate-Related Osteonecrosis of the Jaw in Patients with Osteoporosis

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a rare but severe adverse effect that can occur as a result of bisphosphonate treatment. This study aimed to examine the relationship between <i>PPARγ</i> and <i>PPARGC1A</i> polymorphisms and the BRONJ development in female osteoporosis patients undergoing bisphosphonate treatment. We prospectively conducted this nested case–control study at the Ewha Womans University Mokdong Hospital between 2014 and 2018. We assessed five single-nucleotide polymorphisms (SNPs) of <i>PPARγ</i> and six SNPs of <i>PPARGC1A</i> and performed a multivariable logistic regression analysis to determine the independent risk factors for developing BRONJ. There were a total of 123 patients included in this study and 56 patients (45.5%) developed BRONJ. In the univariate analysis, <i>PPARGC1A</i> rs2946385 and rs10020457 polymorphisms were significantly associated with BRONJ (<i>p</i> = 0.034, <i>p</i> = 0.020, respectively), although the results were not statistically significant in the multivariable analysis. Patients with the combined genotypes of GG in both <i>PPARγ</i> rs1151999 and <i>PPARGC1A</i> rs2946385 showed a 3.03-fold higher risk of BRONJ compared to individuals with other genotype combinations after adjusting for confounders (95% confidence interval (CI): 1.01–9.11). Old age (≥70 years) and duration of bisphosphonate use (≥60 months) increased the risk of BRONJ. The area under the receiver operating characteristic curve for the predicted probability was 0.78 (95% CI: 0.69–0.87, <i>p</i> < 0.001), demonstrating a satisfactory level of discriminatory power. Our study elucidated that <i>PPARγ</i> and <i>PPARGC1A</i> polymorphisms were interactively associated with BRONJ development. These results have potential implications for tailoring personalized treatments for females undergoing bisphosphonate therapy for osteoporosis.